Caverject Powder

CLINICAL PHARMACOLOGY

Alprostadil has a wide variety of pharmacological actions; vasodila- tion and
inhibition of platelet aggregat ion are among the most notable of these effects.
In most animal species tested, alprostadil relaxed retractor penis and corpus
cavernosum urethrae in vitro. Alprostadil also relaxed isolated preparations
of human corpus cavernosum and spongiosum, as well as cavernous arterial segments
contracted by either noradrenaline or PGF2α in vitro. In pigtail
monkeys (Macaca nemestrina), alprostadil increased cavernous arterial
blood flow in vivo. The degree and duration of cavernous smooth muscle
relaxation in this animal model was dose-dependent.

Alprostadil induces erection by relaxation of trabecular smooth muscle and by dilation of cavernosal arteries. This leads to expansion of lacunar spaces and entrapment of blood by compressing the venules against the tunica albuginea, a process referred to as the corporal veno-occlusive mechanism.

Pharmacokinetics

Absorption: For the treatment of erectile dysfunction, alprostadil is
administered by injection into the corpora cavernosa. The absolute bioavailability
of alprostadil has not been determined.

Metabolism: Alprostadil is rapidly converted to compounds which are
further metabolized prior to excretion. Following intravenous administration,
approximately 80% of circulating alprostadil is metabolized in one pass through
the lungs, primarily by beta- and omega-oxidation. Hence, any alprostadil entering
the systemic circulat ion following intracavernosal injection is very rapidly
metabolized. Following intracavernosal injection of 20 micrograms alprostadil,
peripheral levels of the major circulating metabolite, 13,14-dihydro-15-oxo-PGE1,
increased to reach a peak 30 minutes after injection and returned to predose
levels by 60 minutes after injection.

Excretion: The metabolites of alprostadil are excreted primarily by
the kidney, with almost 90% of an administered intravenous dose excreted in
urine within 24 hours post-dose. The remainder of the dose is excreted in the
feces. There is no evidence of tissue retention of alprostadil or its metabolites
following intravenous administration.

Pharmacokinetics in Special Populations

Geriatric: The potential effect of age on the pharmacokinetics of alprostadil
has not been formally evaluated. In patients with acute respiratory distress
syndrome (ARDS), the mean (± SD) pulmonary extraction of alprostadil
was 72% ± 15% in 11 elderly patients aged 65 years or older (mean, 71
± 6 years) and 65% ± 20% in 6 young patients aged 35 years or
younger (mean, 28 ± 5 years).

Gender: The potential influence of gender on the pharmacokinetics of
alprostadil has not been formally studied in healthy subjects. Two studies determined
the pulmonary extraction of alprostadil following intravascular administration
in 23 patients with ARDS. The mean (± SD) pulmonary extraction was 66%
± 20% in 17 male patients and 69% ± 18% in 6 female patients,
suggesting that the pharmacokinetics of alprostadil are not influenced by gender.

Race: The potential influence of race on the pharmacokinetics of alprostadil
has not been formally evaluated.

Renal and Hepatic Insufficiency: The pharmacokinetics of alprostadil
have not been formally examined in patients with renal or hepat ic insufficiency.

Pulmonary Disease: The pulmonary extraction of alprostadil following
intravascular administration was reduced by 15% (66 ± 3.2% vs 78 ±
2.4%) in patients with ARDS compared with a control group of patients with normal
respiratory function who were undergoing cardiopulmonary bypasssurgery. Pulmonary
clearance was found to vary as a function of cardiac output and pulmonary intrinsic
clearance in a group of 14 patients with ARDS or at risk of developing ARDS
following trauma or sepsis. In this study, the extraction efficiency of alprostadil
ranged from subnormal (11%) to normal (90%), with an overall mean of 67%.

Drug-Drug Interactions:

The potential for pharmacokinetic drug-drug interactions between alprostadil and other agents has not been formally studied.

Last reviewed on RxList: 3/3/2008
This monograph has been modified to include the generic and brand name in many instances.